Characteristic features of early atherosclerotic lesions are lipid-filled macrophages, extracellular lipid, and localization of lesions to arterial branches or highly curved arteries. At lesion-prone sites, endothelial permeability to low density lipoprotein (LDL) is enhanced and intimal white blood cells are present. The objective of the proposed research is to evaluate the effect of LDL oxidation and fluid dynamics upon the initial steps of atherogenesis. The proposed research tests two hypotheses: 1) local oxidation of LDL within the arterial wall exacerbates endothelial cell injury which increases monocyte adhesion and LDL transport into the arterial wall, and 2) low and oscillating shear stresses localize injury a) by a direct effect upon endothelial cell function and b) by promoting increased monocyte adhesion. To address the first hypothesis, the investigators will determine the effect of the antioxidants probucol and beta-carotene on LDL transport and endothelial cell expression of adhesion proteins and chemotactic proteins for monocytes in normal and hypercholesterolemic rabbits. Quantitative autoradiography will be used to determine local concentrations of degraded and undegraded LDL around intercostal arteries and major branches of the abdominal aorta. Theoretical models will be used to characterize changes to transport and metabolic properties due to hypercholesterolemia. A panel of monoclonal antibodies will be used to examine endothelial cell expression of adhesion proteins and chemotactic agents, macrophage activation, and the cellular components of early lesions. To address the site of action of the antioxidants, the investigators will measure tissue and LDL levels of antioxidants and determine the effect of antioxidants upon conjugated diene formation by LDL. The second hypothesis will be addressed by correlating fluid dynamics at sites susceptible to lesion development with specific biological changes induced by hypercholesterolemia. Flow visualization will be used to characterize the general features of the flow field, and flush-mounted hot film anemometry will be used to assess wall shear stresses at selected sites of early lesion development. In vitro experiments will be performed to examine the effect of laminar shear stress on the susceptibility of LDL to oxidation. A numerical model of three-dimensional flow and mass transfer around arterial branches will be used to obtain detailed wall shear stress distributions under a variety of flow conditions. Model and experimental wall shear stresses, shear stress gradients, and oscillatory shear indices will be compared with experimentally measured distributions of sites of altered LDL permeability and metabolism and endothelial cell activation. Numerical models of monocyte contact with endothelium will be compared with the spatial distribution of monocyte adhesion protein expression, adherent monocytes and intimal macrophages to assess the extent to which fluid dynamics influences monocyte attachment to the endothelium.